S T U D Y P R O T O C O L
Open Access
Landiolol in patients with septic shock
resident in an intensive care unit
(LANDI-SEP): study protocol for a randomized
controlled trial
Martin Unger
1*, Andrea Morelli
2, Mervyn Singer
3, Peter Radermacher
4, Sebastian Rehberg
5, Helmut Trimmel
6,
Michael Joannidis
7, Gottfried Heinz
8, Vladimír Cerny
9, Pavel Dostál
10, Christian Siebers
11, Fabio Guarracino
12,
Francesca Pratesi
13, Gianni Biancofiore
14, Massimo Girardis
15, Pavla Kadlecova
16, Olivier Bouvet
17, Michael Zörer
1,
Barbara Grohmann-Izay
1, Kurt Krejcy
1, Christoph Klade
1and Günther Krumpl
1Abstract
Background: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements.
Methods: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR≥ 95 bpm) despite a hemodynamic optimization period of 24–36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80–94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80–94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment.
Discussion: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock.
Trial registration: EU Clinical Trials Register; EudraCT,2017-002138-22. Registered on 8 August 2017. Keywords: Septic shock, Sepsis, Beta-blocker, Landiolol, Tachycardia, Randomized controlled trial
* Correspondence:martin.unger@aoporphan.com
1AOP Orphan Pharmaceuticals AG, Wilhelminenstraße 91/II f, 1160 Vienna, Austria
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
In the early phase of septic shock, overwhelming inflam-mation leads to vasodilation and capillary leakage, which decreases cardiac output due to both absolute and relative hypovolemia [1–3]. These alterations trigger massive sym-pathetic activation in the attempt to maintain vital organ perfusion. Tachycardia and vasoconstriction are the hall-marks of this activation and compensate for systemic vasodilatation [4]. In the very early phase of the septic in-sult, tachycardia is the main compensatory mechanism to maintain cardiac output despite the reduction of preload. Accordingly, current sepsis guidelines recommend intra-vascular fluid administration as the first step to counteract hypotension [4]. Compensatory tachycardia implies pre-served baroreceptor and chemoreceptor activity, thus the majority of patients with sepsis rapidly respond to volume administration with a reduction of tachycardia.
However, some patients with sepsis continue to have an elevated heart rate (HR) despite adequate fluid resuscitation. This elevated HR reflects sympathetic overstimulation resulting from dysregulation of the auto-nomic nervous system [5–12] in addition to the effect of exogenous catecholamines [7].
Elevated HR has been associated with a poor outcome, but it is unclear whether it is a surrogate of disease se-verity or whether it plays a pathophysiological role that could be treated to improve patient outcomes [13–16].
Beta-blockers are potential candidates to control HR and numerous animal models provide a rationale for their use during sepsis [17–24]. Despite concerns of hemodynamic decompensation, recent clinical studies using esmolol in patients with sepsis [10, 25–34] suggest that control of HR can be safely achieved with beta1-selective beta-blockers. These studies reported a de-crease in HR with limited reduction of cardiac output, im-proved stroke volume and lactate levels, and stabilization or improvement of organ dysfunction [10, 28–30, 32]. Furthermore, the combined use of beta-blockers and vasopressors appears to be safe and does not appear to in-crease the need for vasopressor support or impair micro-circulation [26, 27, 34]. However, all of the previously reported studies were conducted in single centers with relatively small sample sizes and only one study included a Caucasian population.
Landiolol, the beta-blocker used in our study, is a highly beta1-selective, ultrashort-acting beta-blocker that could be ideally suited for the treatment of critically ill patients due to its limited hypotensive effect [35–38].
The aim of this multicenter, prospective, controlled study is to demonstrate that the administration of the ultrashort-acting beta-blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minutes [bpm]) is effective in reducing and main-taining HR without increasing vasopressor requirements.
Methods/Design
Study design and objective
This is a phase IV, multicenter, prospective, randomized, open-label, controlled study on landiolol in a septic shock population (as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria [39]) hospitalized in an intensive care unit (ICU). The study duration is expected to be 24 months from first patient enrolled until completion of the final visit for the last patient. Participating centers are listed in Table 1.
The study objective is to compare the percentage of patients with a HR response (defined as HR within the target range of 80–94 bpm) and maintenance thereof without an increase in vasopressor requirements within the first 24 h of treatment, and to further assess efficacy and safety in the two treatment arms: standard of care treatment and landiolol (landiolol group) or standard of care treatment alone (control group).
Additional file 1 contains the completed Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist.
Study population
This study will enroll a total of 200 patients with septic shock and elevated HR (≥ 95 bpm) despite a hemodynamic optimization phase of at least 24 h but a maximum of 36 h in which they received adequate fluid resuscitation and continuous vasopressor treatment (ac-cording to the Surviving Sepsis Campaign Guidelines 2016 [40]). Detailed inclusion and exclusion criteria are displayed in Table2.
Randomization, blinding, and treatment allocation
Patients fulfilling the selection criteria are randomized in a 1:1 ratio to one of the two groups (landiolol or control) after informed consent, as required by local law, has been obtained. The presence of atrial fibrillation in the hemodynamic optimization period is used as a stratifica-tion factor for randomizastratifica-tion. As this is an open label study, investigators and other study personnel will not be blinded to the treatment.
Study drug
Lyophilized landiolol hydrochloride 300 mg (Rapibloc Lyo, 300 mg) is to be reconstituted in 50 mL of 0.9% NaCl to a concentration of 6 mg/mL before use.
Treatments Landiolol group
Patients in the landiolol group begin continuous infusion with landiolol within 2 h after randomization at a start-ing dose of 1 mcg/kg/min. The dose is to be progres-sively increased at increments of 1 mcg/kg/min to a
maximum of 40 mcg/kg/min at intervals of at least 20 min to obtain and maintain a HR of 80–94 bpm. Landiolol must be infused continuously to maintain the target HR until one the following events occurs: discon-tinuation of vasopressor infusion; death; a serious ad-verse event (AE) attributable to the study drug that necessitates study drug discontinuation as determined by the investigator; patient discharge from the ICU; or day 28 of study participation.
Control group
Patients in the control group receive standard of care treatment according to the Surviving Sepsis Campaign Guidelines 2016 [40], which does not specify a target for HR control. Patients in the control group are to be with-drawn from the study if they receive beta-blocker treatment.
Patient assessments
Heart rate, blood pressure, and body temperature will be documented hourly for the first 24 h after ment start and every 12 h thereafter in both treat-ment groups, and additionally at every dose change of landiolol in the landiolol group. Clinical laboratory analysis including blood gas analysis will be per-formed daily for the first four days of the study. Se-quential Organ Failure Assessment (SOFA) score will be assessed daily for the first four days and every third day thereafter. If performed, hemodynamic pa-rameters (CO, CI, GEDI, ELWI, PAOP, MPAP, LVEF, TAPSE, VTI) obtained by PICCO/FloTrac, Swan-Ganz catheter or Cardiac Echo will be documented. Con-comitant medication and AE will be documented over the entire study period. Measurements and assess-ments performed in both groups are listed in Fig. 1
in the completed SPIRIT figure.
Table 1 List of participating centers and ethics committee approvals
Participating center PI Central Ethics committee Reference number Approval date Medical University Vienna, Department
of Internal Medicine II. Division of Cardiology
Gottfried Heinz, MD Ethics Committee, Medical University Vienna
ECS 1805/2017 15 September 2017
Medical University Innsbruck, Division of Emergency Medicine and Intensive Care, Department Internal Medicine
Michael Joannidis, MD
State Hospital Wiener Neustadt, Department of Anesthesiology, Emergency Medicine and General Intensive Care
Helmut Trimmel, MD, MSc
University Hospital Greifswald, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine
Sebastian Rehberg, MD Ethics Committee, University Hospital Greifswald
FFV 06/17 15 February 2018
University Hospital Munich, Department of Anesthesiology
Christian Siebers, MD University Hospital Hradec Králové,
Department of Anesthesiology, Resuscitation and Intensive Medicine
Pavel Dostál, MD, PhD, MBA Ethics Committee, University Hospital Hradec Králové
201801 I126M 07 November 2017
Masaryk Hospital, Department of Anesthesiology, Perioperative Medicine and Intensive Care
VladimírČerný, MD, PhD, FCCM
University Hospital La Sapienza, Department of Anesthesiology and Intensive Care
Andrea Morelli, MD. Ethics Committee, University Hospital La Sapienza
4846 08 February 2018
Azienda Ospedaliero Universitaria Pisana, Department of Anesthesiology and Resuscitation 5
Fabio Guarracino, MD
Azienda Ospedaliero Universitaria Pisana, Department of Anesthesiology and Resuscitation 6
Francesca Pratesi, MD
University School of Medicine Pisa, Department of Anesthesiology and Transplant Intensive Care Unit
Gianni Biancofiore, MD
University Hospital Modena,
Department of Anesthesia and Intensive Care
Endpoints
The primary efficacy endpoint is HR response (HR = 80–94 bpm) and maintenance thereof without increase in vasopressor requirements during the first 24 h after treatment start.
Secondary efficacy endpoints will consist of ICU and 28-day mortality, ICU and hospital stay duration, SOFA score, and inotrope and vasopressor support requirements. Efficacy and safety endpoints are listed in Table 3.
Data collection
Data will be collected and entered into the electronic data capture system by trained study personnel (investi-gators and study nurses).
Sample size
Sample size estimation is based upon the assumption that 60% of patients in the landiolol group reach the pri-mary endpoint versus 40% of patients in the control group. The sample size of 200 patients will provide 80% power to demonstrate a statistically significant difference (upon standard level alpha = 0.05) between the treatment groups using a Chi-square test. The sample size in the study by Morelli et al. [10] was adequate considering that to detect a 20% change in HR with a power of 80% at a level of significance of alpha = 0.05, 64 patients per group would have been required. In order to detect the binary primary endpoint of our study an additional 36 patients per group are required.
Statistical analysis
The hypothesis that Group L is superior to Group C in proportion of patients who reached the primary end-point will be demonstrated if the lower limit of the two-sided 95% Newcombe confidence interval of differ-ence pL-pC is above zero, where pL and pC are percent-ages of patients who reached the primary endpoint in Group L and Group C, respectively. P values based on Cochran–Mantel–Haenszel (according to SAS® termin-ology) will be presented together with the confidence intervals to evaluate statistical significance of association between treatment group and outcome after adjustment for the stratification group. For the purpose of explora-tory analysis, the individual criteria of the primary endpoint, heart rate response (i.e. HR = 80–94 bpm) reached (also defined as secondary endpoint), heart rate response reached and maintained and no increase in vasopressor requirements during the first 24 h, will be compared separately between treatment groups. Additional subgroup and sensitivity analyses will have exploratory character and will be defined in all details in the SAP.
Secondary endpoints with continuous, ordinal, and binary variables measured at multiple time-points will be analyzed as longitudinal data by linear, ordinal logistic, logistic, or log-binomial regression models with repeated measures. Covariates used in the models will be (but not limited to) treatment, visit, stratification group, and interaction treatment/visit. For continuous variables baseline value of the outcome variable will be a covariate as well. Distribution of data and a feasibility check of planned analyses will be performed before finalization of SAP and alternative statistical methods will be defined if assumptions on the application of the planned methods are not met (e.g. ln-transformation of data, non-para-metric method, or other alternative way). ICU mortality and 28-day mortality will be analyzed using the same methods as for the primary endpoint. Duration of ICU stay and duration of hospital stay (in survivors/
Table 2 Inclusion/exclusion criteria
Inclusion criteria 1. Informed consent
2. Age≥ 18 years 3. Confirmed septic shock:
a. Confirmed or suspected infection
b. Acute increase of≥ 2 points on SOFA Score
c. Need for continuous vasopressor therapy to maintain a mean arterial pressure (MAP) of > 65 mmHg despite adequate fluid resuscitation
d. Blood lactate > 2 mmol/L (18 mg/dL)a
4. Tachycardia and/or tachyarrhythmia with heart rate≥ 95 bpm 5. Norepinephrine infusion rate≥ 0.2 μg/kg/min at the time of study
inclusion
6. Patients must have undergone a hemodynamic optimization period of at least 24 h but a maximum of 36 h, during which period they received continuous vasopressor treatment and standard treatment for septic shock according to the SSCG 2016 guidelines
a
Presence of blood lactate > 2 mmol/L (18 mg/dL) and increase of≥ 2 points on SOFA score are mandatory for the diagnosis of septic shock, but must not necessarily be present at the time of study inclusion Exclusion criteria:
1. Any form of compensatory tachycardia
2.β-blocker treatment within 72 h before randomization 3. Sick sinus syndrome, or second or third degree AV block 4. Patients with any form of cardiac pacing
5. A known serious cardiovascular condition such as ischemic stroke or transient ischemic attack within the last six months, or pre-existing heart failure NYHA class III or IV
6. Cardiogenic shock 7. MAP < 65 mmHg
8. Known pulmonary hypertension
9. Known terminal illness other than septic shock with expected patient’s survival < 28 days
10. Known presence of an advanced condition to withhold life-sustaining treatment
11. Patients for whom a“Do Not Resuscitate” (DNR) order exists 12. Known sensitivity to any component of the study medication (e.g.
landiolol, mannitol)
13. Participation in a clinical drug trial within 30 days before randomization
14. Any condition that, in the investigator’s opinion, makes the individual unsuitable for study participation (to be documented) 15. Pregnant or breast-feeding patients
16. Untreated pheochromocytoma NYHA New York Heart Association
non-survivors) will be analyzed as time-to-event data (using Kaplan–Meier curve and using log-rank test or Wilcoxon test and/or proportional hazards regression model if appropriate).
For secondary analyses, no multiplicity adjustment is planned; therefore, a higher rate of type-I error must be considered in interpretation of results of secondary ana-lyses. The analysis of secondary endpoints/analyses can provide supportive evidence related to the primary ob-jective, but no confirmatory conclusion based on sec-ondary analyses can be done.
Discussion
Despite intensive research, morbidity and mortality of patients with sepsis remain high [39]. Hence, novel therapeutic concepts are urgently needed. Recently, the use of beta-blockers during sepsis has been suggested [10,28–30,32,41]. This represents a true innovation, as current guidelines recommend beta-mimetics [40]. The
potential benefits of beta-blockers are most likely due to their pleotropic effects and include myocardial protec-tion, modulation of inflammatory processes, and im-provements in organ functions [3, 22, 42–44]. However, it is still unclear which patients would benefit most from this intervention.
Morelli et al. [10] (and later others [28–30, 32]) showed that a HR reduction in patients with septic shock, after adequate resuscitation with fluids, vasopres-sors, and inotropes, was not associated with an increase in AEs and did not trigger an increase in vasopressor support. As in the original protocol by Morelli et al. [10], the target HR in the present study is < 95 bpm, which is based on studies showing poorer patient out-comes when this threshold is exceeded and studies showing good tolerance after achieving this target with beta-blockers [7,11,45–48]. More recently, several stud-ies conducted in China [28–30,32] that selected a simi-lar HR target showed good tolerance of the beta-blocker
treatment. Therefore, the HR target of < 95 bpm seems appropriate for further comparison and optimal with respect to feasibility and tolerance.
In order to minimize the risk of hemodynamic com-promise, patients are only included in the study after at least 24 h of adequate fluid resuscitation and vasopressor support. In addition, landiolol is started at a low dose of 1 mcg/kg/min (as supported by landiolol sepsis [49], post-operative [50], and heart failure studies [51]) and titration is performed conservatively at 20-min intervals (5 half-lives) [35]. The HR target should be reached within the first 24 h, as supported by published data [28–30,32].
Esmolol is the beta-blocker that has been most frequently evaluated in patients with sepsis, as its pharmacokinetic profile allows for rapid titration when used intravenously [10,27–29,31]. However, landiolol has demonstrated a more favorable pharmacokinetic and pharmacodynamic profile than esmolol [52–55]. Landiolol has a faster onset (1 min vs 2 min) and shorter half-life (4 min vs 9 min) than esmolol, which should allow for more rapid titration and enhanced safety [35]. Further-more, the beta1 selectivity of landiolol is eight times higher than that of esmolol, resulting in a beta1/beta2 ra-tio of 255 [35]. This provides landiolol with more pro-found negative chronotropic effects and a lesser degree of negative inotropic and hypotensive action [36–38,56].
This study will investigate whether HR control using the short-acting beta-blocker landiolol is feasible, safe, and effective in patients with septic shock and persist-ent tachycardia, and provide a better understanding of the potential role of beta-blockers in this patient population.
Trial status
Protocol version 3.0 dated 3 January 2018. The first par-ticipant was enrolled on 24 February 2018.
Additional file
Additional file 1:Checklist_SPIRIT_guidelines.pdf, Checklist of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. (PDF 129 kb)
Abbreviations
APACHE II:Acute Physiology and Chronic Health Evaluation II;
AV: Atrioventricular; Bpm: Beats per minute; CI: Cardiac Index; CO: Cardiac output; ELWI: Extravascular lung water index; GEDI: Global end-diastolic vol-ume index; HR: Heart rate; ICU: Intensive care unit; LVEF: Left ventricular ejection fraction; MPAP: Mean pulmonary arterial pressure; PAOP: Pulmonary arterial occlusion pressure; NYHA: New York Heart Association; PICCO: Pulse contour cardiac output; SOFA: Sequential Organ Failure Assessment; SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials; TAPSE: Tricuspid annular plane systolic excursion; VTI: Velocity time integral Acknowledgements
We would like to thank Dr. Alain Rudiger for his support and feedback during the writing of the study protocol and this publication.
Funding
This study is sponsored by AOP Pharmaceuticals AG and co-sponsored by Amomed Pharma GmbH.
Availability of data and materials Not applicable.
Authors’ contributions
MU, AM, MS, PR, SR, HT, MJ, KK, GH, VC, PD, CS, FG, FP, GB, MG, BGI, MZ, CKL, and GK contributed to the design of the trial. PK provided the statistical analysis. MU and OB drafted the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Approvals of central ethics committees are listed in Table1. Consent for publication
Not applicable. Competing interests
MU, GK, BGI, MZ, KK, and CK are employees of AOP Pharmaceuticals AG, OB is an employee of Amomed Pharma GmbH.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author details
1AOP Orphan Pharmaceuticals AG, Wilhelminenstraße 91/II f, 1160 Vienna, Austria.2Department of Anesthesiology and Intensive Care, University Hospital La Sapienza, Policlinico Umberto I, Rome, Italy.3Intensive Care Medicine, University College London, London, UK.4Institute of
Anesthesiologic Pathophysiology and Process Engineering, Ulm University Hospital, Ulm, Germany.5Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Greifswald, Greifswald, Germany.6Department of Anesthesiology, Emergency Medicine and General Intensive Care, State Hospital Wiener Neustadt, Wiener Neustadt, Austria. 7Division of Emergency Medicine and Intensive Care, Department Internal Medicine, Medical University Innsbruck, Innsbruck, Austria.8Department of Internal Medicine II, Division of Cardiology, Intensive Care Unit, Medical University General Hospital, Vienna, Austria.9Department of Anesthesiology, Perioperative Medicine and Intensive Care, Masaryk Hospital, Usti Nad Labem, Czech Republic.10Department of Anesthesiology, Resuscitation and
Table 3 Efficacy and safety endpoints
Primary endpoint:
• HR response (i.e. HR = 80–94 bpm) and maintenance thereof and no increase in vasopressor requirements during the first 24 h after treatment start
Secondary endpoints:
• Change in vasopressor requirements over the study period (dose and duration)
• HR response (i.e. HR = 80–94 bpm) during the first 24 h after treatment start
• 28-day mortality (all cause) • ICU mortality (all cause)
• Duration of ICU stay (survivors/non-survivors) • Duration of hospital stay (survivors/non-survivors)
• SOFA score (as long as the patient is treated with vasopressors) on days 1, 2, 3, 4, 7, 10, 13, 16, 19, 22, 25, and 28
• Daily inotropic requirements (as long as the patient is treated with vasopressors)
Safety endpoints:
• Incidence rate of bradycardic episodes requiring intervention • Incidence of adverse events (AE)
Intensive Medicine, University Hospital Hradec Králové, Hradec Králové, Czech Republic.11Department of Anesthesiology, University Hospital Munich, Munich, Germany.12Department of Anesthesiology and Resuscitation 5, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.13Department of Anesthesiology and Resuscitation 6, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.14Division of Transplant Anesthesia and Critical Care, University School of Medicine Pisa, Pisa, Italy.15Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy.16Aixial s.r.o, Brno, Czech Republic.17Amomed Pharma GmbH, Vienna, Austria.
Received: 5 June 2018 Accepted: 26 October 2018
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